The human gut harbors an enormously diverse community of microorganisms collectively referred to as the microbiome. This microbiome has co-evolved with humans over half a billion years to assist in critical host metabolic and immune function. The impact of changes in the microbiome on disease states as diverse as diabetes, obesity, inflammatory bowel disease, epilepsy, and multiple sclerosis is only now being recognized. It is clear that human immunodeficiency virus (HIV) infection has profound effects on the intestinal mucosal environment with one of the hallmarks of HIV infection being a rapid and profound depletion of CD4+ T cells within gut associated lymphoid tissue (GALT). Despite this, there is a paucity of information regarding the changes that occur in the intestinal microbiota in HIV infection and the potential effects of these changes on host immunity and HIV disease progression. It is believed that HIV infection results in intestinal inflammation and increased intestinal mucosal permeability with subsequent translocation of luminal microbial products into the systemic circulation. This microbial translocation drives chronic immune activation, which results in T cell exhaustion and HIV disease progression. The mechanism by which HIV induces intestinal epithelial dysfunction and microbial translocation remains incompletely understood. Even less is known about how gut microbial populations may influence, or be influenced by, this process. Still, it has been shown that enteric microbiota in humans and nonhuman primates can be significantly altered early in infection by lentiviral-mediated disease. Abnormal microbiota are strongly associated with intestinal inflammation in inflammatory bowel disorders with data suggesting a causal role in gut inflammation. This suggests that the microbiome may play a direct role in mediating intestinal dysfunction. It is therefore critical to develop a more detailed understanding of the impact of alterations in the intestinal microbiome on HIV-associated intestinal dysfunction and disease progression. This proposal seeks to define the role of the enteric microbiome and virome in HIV infection by using high-throughput next generation sequencing (NGS) to conduct a comprehensive survey of dynamic changes in gut microbial populations using stool, tissue and plasma from human subjects. We will define novel components of the human intestinal microbiome in the uninfected state as well as alterations that occur with advanced HIV/AIDS and upon initiation of antiretroviral therapy (ART). We will link the microbiome in stool with microbial species associated with the intestinal tissue and explore the mechanism by which tissue associated microbes contribute to HIV disease progression. Finally, we will compliment these studies with an analysis of the mechanism by which changes in the enteric microbiome contribute to HIV disease progression. These studies will result in a more detailed fundamental understanding of the relationship between the intestinal ecology and its role in HIV disease progression and also identify potential new interventions targeting the intestinal microbiome to treat the long term inflammatory consequences of HIV infection.